The Role of NADPH Oxidase and Neuronal Nitric Oxide Synthase in Zinc-Induced Poly(ADP-ribose) Polymerase Activation and Cell Death in Cortical Culture
Abstract
In the present study, we examined the role and the mechanism of poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) activation in zinc-induced cell death in cortical culture. After brief exposure to 400 microM zinc, cortical cells exhibited DNA fragmentation, increased poly(ADP-ribosyl)ation, and decreased levels of nicotinamide adenine dinucleotide (NAD) and ATP and subsequently underwent cell death. Inhibitors of PARP/PARG attenuated both zinc-induced NAD/ATP depletion and cell death, thereby implicating the PARP/PARG cascade in these processes. The zinc-inducible enzymes NADPH oxidase and neuronal nitric oxide synthase (nNOS) contributed to PARP activation as their inhibitors attenuated zinc-induced poly(ADP-ribosyl)ation. Levels of nitric oxide and nitrites increased following zinc exposure, consistent with NOS activation. In addition, Western blots and RT-PCR analysis revealed that protein and mRNA levels of nNOS specifically increased following zinc exposure in a manner similar to that of NADPH oxidase. The present study demonstrates that induction of NADPH oxidase and nNOS actively contributes to PARP/PARG-mediated NAD/ATP depletion and cell death induced by zinc in cortical culture.
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Zinc influx into neurons leads to nitric oxide generation, PARP-1 activation, and cell death.
“Like Ca 2+ influx, zinc influx into neurons leads to the generation of nitric oxide and subsequent activation of PARP-1 and cell death [114].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [114]
Cites
Koh, J. Y., & Choi, D. W. (1987) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(87)90041-0 · Cited by 1,267 · see citing works
Self-citationRole of poly(ADP-ribose) formation in DNA repair
Satoh, M. S., & Lindahl, T. L. (1992) · Nature · doi:10.1038/356356a0 · Cited by 1,181 · see citing works
Nitric Oxide Activation of Poly(ADP-Ribose) Synthetase in Neurotoxicity
Zhang, J., Dawson, V. L., Dawson, T. M., & Snyder, S. H. (1994) · Science · doi:10.1126/science.8080500 · Cited by 1,118 · see citing works
The Role of Zinc in Selective Neuronal Death After Transient Global Cerebral Ischemia
Koh, J., Suh, S. W., Gwag, B. J., He, Y. Y., Hsu, C. Y., & Choi, D. W. (1996) · Science · doi:10.1126/science.272.5264.1013 · Cited by 1,070 · see citing works
Self-citationPoly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia
Eliasson, M. J. L., Sampei, K., Mandir, A. S., Hurn, P. D., Traystman, R. J., Bao, J., Pieper, A. A., Wang, Z., Dawson, T. M., Snyder, S. H., et al. (1997) · Nature Medicine · doi:10.1038/nm1097-1089 · Cited by 1,019 · see citing works
Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion
Ha, H. C., & Snyder, S. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.24.13978 · Cited by 904 · see citing works
Poly(ADP-ribose) polymerase: a molecular nick-sensor
de MURCIA, G., & Murcia, J. M. (1994) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(94)90280-1 · Cited by 801 · see citing works
Poly(ADP-Ribose) in the Cellular Response to DNA Damage
Berger, N. A. (1985) · Radiation Research · doi:10.2307/3576299 · Cited by 777 · see citing works
Choi, D. W., & Koh, J. Y. (1998) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.21.1.347 · Cited by 754 · see citing works
Self-citationRole of poly(ADP-ribose) synthetase in inflammation and ischaemia–reperfusion
Szabó, C., & Dawson, V. L. (1998) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(98)01193-6 · Cited by 685 · see citing works
Oxidative Stress in Brain Ischemia
Love, S. (1999) · Brain Pathology · doi:10.1111/j.1750-3639.1999.tb00214.x · Cited by 684 · see citing works
Pathological implications of nitric oxide, superoxide and peroxynitrite formation
Beckman, J. S., & Crow, J. P. (1993) · Biochemical Society Transactions · doi:10.1042/bst0210330 · Cited by 676 · see citing works
Yamamoto, H., Uchigata, Y., & Okamoto, H. (1981) · Nature · doi:10.1038/294284a0 · Cited by 530 · see citing works
Poly (ADP-ribose) polymerase, nitric oxide and cell death
Pieper, A. A. (1999) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(99)01292-4 · Cited by 521 · see citing works
Sensi, S. L., Yin, H. Z., Carriedo, S. G., Rao, S. S., & Weiss, J. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.5.2414 · Cited by 408 · see citing works
Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice
Dawson, V., Kizushi, V., Huang, P., Snyder, S. H., & Dawson, T. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-08-02479.1996 · Cited by 406 · see citing works
An improved cycling assay for nicotinamide adenine dinucleotide
Bernofsky, C., & Swan, M. (1973) · Analytical Biochemistry · doi:10.1016/0003-2697(73)90094-8 · Cited by 385 · see citing works
ADP-ribosylation of proteins. Enzymology and biological significance.
Althaus, F. R., & Richter, C. (1987) · PubMed · Cited by 371 · see citing works
Sheline, C. T., Behrens, M. M., & Choi, D. W. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-09-03139.2000 · Cited by 369 · see citing works
Eliasson, M. J. L., Huang, Z., Ferrante, R. J., Sasamata, M., Molliver, M. E., Snyder, S. H., & Moskowitz, M. A. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-14-05910.1999 · Cited by 366 · see citing works
Translocation of zinc may contribute to seizure-induced death of neurons
Frederickson, C. J., Hernández, M. D., & McGinty, J. F. (1989) · Brain Research · doi:10.1016/0006-8993(89)90199-6 · Cited by 345 · see citing works
Induction and Activation by Zinc of NADPH Oxidase in Cultured Cortical Neurons and Astrocytes
Noh, K., & Koh, J. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-23-j0001.2000 · Cited by 335 · see citing works
Self-citationImportance of Poly(ADP-Ribose) Glycohydrolase in the Control of Poly(ADP-Ribose) Metabolism
Davidovic, L., Vodenicharov, M. D., Affar, E. B., & Poirier, G. G. (2001) · Experimental Cell Research · doi:10.1006/excr.2001.5263 · Cited by 326 · see citing works
Tønder, N., Johansen, F. F., Frederickson, C. J., Zimmer, J., & Diemer, N. H. (1990) · Neuroscience Letters · doi:10.1016/0304-3940(90)90002-q · Cited by 301 · see citing works
Molecular and biochemical features of poly (ADP-ribose) metabolism
Lautier, D., Lagueux, J., Thibodeau, J., M�nard, L., & Poirier, G. G. (1993) · Molecular and Cellular Biochemistry · doi:10.1007/bf01076101 · Cited by 301 · see citing works
DNA strand breaks, NAD metabolism, and programmed cell death
Carson, D. A., Seto, S., Wasson, D. B., & Carrera, C. J. (1986) · Experimental Cell Research · doi:10.1016/0014-4827(86)90028-5 · Cited by 300 · see citing works
Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury
Suh, S. W., Chen, J. W., Motamedi, M., Bell, B. A., Listiak, K., Pons, N. F., Danscher, G., & Frederickson, C. J. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02095-8 · Cited by 287 · see citing works
Kim, Y. H., Kim, E. Y., Gwag, B. J., Sohn, S., & Koh, J. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00313-3 · Cited by 266 · see citing works
Self-citationHeller, B., Wang, Z., Wagner, E. F., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.19.11176 · Cited by 266 · see citing works
Characterization of polymers of adenosine diphosphate ribose generated in vitro and in vivo
Álvarez-González, R., & Jacobson, M. K. (1987) · Biochemistry · doi:10.1021/bi00385a042 · Cited by 244 · see citing works
Poly(ADP-ribose) catabolism in mammalian cells exposed to DNA-damaging agents
Álvarez-González, R., & Althaus, F. R. (1989) · Mutation Research/DNA Repair · doi:10.1016/0921-8777(89)90012-8 · Cited by 224 · see citing works
Nitric oxide synthases: targets for therapeutic strategies in neurological diseases
Chabrier, P. E., Demerlé-Pallardy, C., & Auguet, M. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050353 · Cited by 215 · see citing works
Structure and function of poly(ADP-ribose) polymerase
de MURCIA, G., Schreiber, V., Molinete, M., Saulier, B., Poch, O., Masson, M., Niedergang, C., & Murcia, J. M. (1994) · Molecular and Cellular Biochemistry · doi:10.1007/bf00928438 · Cited by 208 · see citing works
Itoh, Y., Ma, F. H., Hoshi, H., Oka, M., Noda, K., Ukai, Y., Kojima, H., Nagano, T., & Toda, N. (2000) · Analytical Biochemistry · doi:10.1006/abio.2000.4859 · Cited by 203 · see citing works
Sims, J. L., Berger, S. J., & Berger, N. A. (1983) · Biochemistry · doi:10.1021/bi00291a019 · Cited by 199 · see citing works
Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death
Ying, W., Sevigny, M. B., Chen, Y., & Swanson, R. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211202598 · Cited by 199 · see citing works
Neonatal Mice Lacking Neuronal Nitric Oxide Synthase Are Less Vulnerable to Hypoxic–Ischemic Injury
Ferriero, D. M., Holtzman, D. M., Black, S. M., & Sheldon, R. A. (1996) · Neurobiology of Disease · doi:10.1006/nbdi.1996.0006 · Cited by 192 · see citing works
The Complex Role of Nitric Oxide in the Pathophysiology of Focal Cerebral Ischemia
Dalkara, T., & Moskowitz, M. A. (1994) · Brain Pathology · doi:10.1111/j.1750-3639.1994.tb00810.x · Cited by 171 · see citing works
Sensi, S. L., Yin, H. Z., & Weiss, J. H. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00277.x · Cited by 158 · see citing works
Characterization of Zinc-Induced Neuronal Death in Primary Cultures of Rat Cerebellar Granule Cells
Manev, H., Kharlamov, E. A., Uz, T., Mason, R. P., & Cagnoli, C. M. (1997) · Experimental Neurology · doi:10.1006/exnr.1997.6510 · Cited by 138 · see citing works
NITRIC OXIDE: ROLE IN NEUROTOXICITY
Dawson, V. L. (1995) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.1995.tb02005.x · Cited by 137 · see citing works
Poly(ADP‐Ribose) Synthetase Activation: An Early Indicator of Neurotoxic DNA Damage
Zhang, J., Pieper, A. A., & Snyder, S. H. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65031411.x · Cited by 117 · see citing works
Endres, M., Scott, G. S., Namura, S., Salzman, A. L., Huang, P. L., Moskowitz, M. A., & Szabó, C. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00224-9 · Cited by 116 · see citing works
Pieper, A. A., Blackshaw, S., Clements, E. E., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1845 · Cited by 115 · see citing works
Role of Bound Zinc in Dimer Stabilization but Not Enzyme Activity of Neuronal Nitric-oxide Synthase
Hemmens, B., Goessler, W., Schmidt, K., & Mayer, B. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005976200 · Cited by 108 · see citing works
Samdani, A. F., Newcamp, C., Resink, A., Facchinetti, F., Hoffman, B. E., Dawson, V. L., & Dawson, T. M. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-12-04633.1997 · Cited by 97 · see citing works
Zinc-induced neuronal death in cortical neurons.
Lobner, D., Canzoniero, L. M. T., Manzerra, P., Gottron, F. J., Ying, H. S.-C., Knudson, C. M., Tian, M., Dugan, L. L., Kerchner, G. A., Sheline, C. T., et al. (2000) · PubMed · Cited by 80 · see citing works
The poly(ADP-ribose) glycohydrolase inhibitor gallotannin blocks oxidative astrocyte death
Ying, W., & Swanson, R. A. (2000) · Neuroreport · doi:10.1097/00001756-200005150-00007 · Cited by 77 · see citing works
Neuronal accumulation of poly(ADP‐ribose) after brain ischaemia
Love, S., Barber, & Wilcock (1999) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.1999.00179.x · Cited by 75 · see citing works
Cosi, C., & Marien, M. R. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07998.x · Cited by 70 · see citing works
Masahiro, N. I. W. A., Inao, S., Takayasu, M., 河合達巳, Kajita, Y., Nihashi, T., Kabeya, R., Sugimoto, T., & Yoshida, J. (2001) · Neurologia medico-chirurgica · doi:10.2176/nmc.41.63 · Cited by 58 · see citing works
Komatsu, N., Nakagawa, M., Oda, T., & Muramatsu, T. (2000) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a022775 · Cited by 56 · see citing works
Holtz, M. L., Craddock, S. D., & Pettigrew, L. C. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02140-0 · Cited by 55 · see citing works
Higuchi, Y., Hattori, H., Hattori, R., & Furusho, K. (1996) · Brain and Development · doi:10.1016/0387-7604(96)00019-8 · Cited by 54 · see citing works
Biochemical properties and function of poly(ADP-ribose) glycohydrolase
Desnoyers, S., Shah, G. M., Brochu, G., et al. (1995) · Biochimie · doi:10.1016/0300-9084(96)88156-9 · Cited by 36 · see citing works
Snider, B. J., Choi, J., Turetsky, D. M., Canzoniero, L. M. T., Sensi, S. L., Sheline, C. T., Wang, X., Yu, S. P., & Choi, D. W. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00311-0 · Cited by 30 · see citing works
Baader, S. L., Bucher, S., & Schilling, K. (1997) · Developmental Neuroscience · doi:10.1159/000111217 · Cited by 30 · see citing works
Chemotherapeutically induced DNA damage, ATP depletion, and the apoptotic biochemical cascade.
Ds, M., & Gk, S. (1997) · PubMed · Cited by 25 · see citing works
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Marreiro, D., Cruz, K., Morais, J., Beserra, J., Severo, J., & De Oliveira, A. (2017) · Antioxidants · doi:10.3390/antiox6020024 · Cited by 679 · see citing works
Suh, S. W., Gum, E. T., Hamby, A. M., Chan, P. H., & Swanson, R. A. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30077 · Cited by 419 · see citing works
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- Authors
- Kim, Y.-H., & Koh, J.-Y.
- Affiliations
- Sejong University (KR)
- University of Ulsan (KR)
- Corresponding author
- Koh, Jae-Young
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 177
- Issue
- 2
- Pages
- 407-418
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W1985584861
- Cited by
- 163
- References
- 58
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 7 · 2021: 3 · 2020: 6 · 2019: 10 · 2018: 4 · 2017: 9 · 2016: 11 · 2015: 3 · 2014: 7 · 2013: 7 · 2012: 7
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Keywords
- zinc toxicity, poly(ADP-ribose) polymerase, poly(ADP-ribose) glycohydrolase, NADPH oxidase, neuronal nitric oxide synthase, neuronal cell death, DNA fragmentation, poly(ADP-ribosyl)ation, nitric oxide, cortical neurons, oxidative stress
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Adenosine Triphosphate, Animals, Astrocytes, Cells, Cultured, Cerebral Cortex, Enzyme Activation, Enzyme Induction, Enzyme Inhibitors, Glycoside Hydrolases, NAD, Neurons, Nitric Oxide, Poly(ADP-ribose) Polymerases, Tyrosine, Zinc, Apoptosis, Coculture Techniques, Nitric Oxide Synthase, NADPH Oxidases, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III, DNA Fragmentation
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